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Smallpox Scares

Hugh Pennington

After two or three days of illness, pains of extraordinary severity develop. The head feels as though the skull is opening and shutting. Excruciating backache feels like the bones grinding together. There is complete prostration but also persistent sleeplessness and an unnatural clearness of intellect – as though none of these sufferings should be missed. The breath has a sickly odour, ‘unique in the catalogue of nasty smells’ according to T.F. Ricketts’s Diagnosis of Smallpox (1908) – Ricketts was medical superintendent of the Smallpox Hospitals and River Ambulance Service of the Metropolitan Asylums Board. The haemorrhagic rash matures on the tenth day; death occurs about this time.

A quarter of a century has gone by since the last natural case of smallpox anywhere in the world. Ali Maow Maalin, a cook at the hospital in Merca, Somalia, and sometime vaccinator in a World Health Organisation eradication team, developed his rash on 27 October 1977. After this final hiccup smallpox joined the dodo and the dinosaur as life-forms extinct in the natural world.

Maalin was lucky: his case was mild. To be absolutely certain that the world was smallpox-free, surveillance went on for two years after his illness. There were no more ‘natural’ cases and on 8 May 1980, Resolution WHA33.3 was signed at the eighth plenary meeting of the 33rd World Health Assembly. It declared that ‘the world and all its people’ had ‘won freedom from smallpox . . . which only a decade ago was rampant in Africa, Asia and South America’.

Smallpox was only extinct by resolution and in ‘nature’, however. It lived on in laboratories in frozen form. It still does. There is currently concern that some of it may have fallen into the wrong hands. Laboratory stocks of smallpox are just as malevolent as their natural counterparts. The last human smallpox infections anywhere in the world were contracted from such stocks and occurred not in Africa, Asia or South America, but in England.

In 1978 Henry Bedson was professor of medical microbiology at Birmingham University. His father, Sir Samuel, had also been a microbiologist, whose work on psittacosis had been recognised by a proposal to call the group of organisms to which it belonged Bedsonia. Henry Bedson had been trained as a virologist by the doyen of British smallpox experts, Allan Downie of Liverpool University. Downie was the eighth son of a fisherman from Rosehearty in North-East Scotland. He had an identical twin, Ricky. Together they won all the prizes and ended up with identical marks when they qualified simultaneously with first-class honours from medical school. On graduation day in 1923 the class piled into the Kirkgate Bar across from Aberdeen’s Marischal College. Ricky had got to the counter but Allan was still at the door when an emissary from my predecessor but one (Aberdeen bacteriology professors don’t retire early) came with orders to ‘get one of the Downie twins’. This is why Allan became a microbiologist and Ricky a general practitioner. In Downie’s day, smallpox work was done on wooden benches in the open laboratory. There were no safety cabinets or safety committees: vaccination was relied on as the control measure. There is a story that when a student wanting a project went to see Downie, he would open a drawer in his desk and pull out an envelope containing dried crusts from a smallpox patient’s rash and tell the student to characterise the virus.

By 1978 things had moved on. The previous autumn, the WHO had told Henry Bedson that his application for his lab to become a Smallpox Collaborating Centre had been rejected. This meant that in the fairly near future his lab’s work on the virus would have to stop. The WHO wanted as few sites as possible handling the virus. They had acceded, however, to his request to continue research until the end of 1978. Their safety inspectors would visit. Henry faced a dilemma. He wanted to finish his current research programme, which was significantly advancing our understanding of smallpox viruses. I had supported his judgment on the importance of this research in the spring when I examined the PhD student carrying it out and recommended that she be given her degree. But Henry was also aware that the laboratory would fail the forthcoming WHO safety inspection and that there would be no money for an upgrade because of its imminent closure. I shared his view about the safety of the lab: when I got back to Scotland I hammered vaccinia into my arm even though I knew that my immunity was good. Smallpox work continued in Birmingham, but the WHO inspectors were unhappy. Correspondence started with Geneva about safety problems. Although Bedson’s laboratory was not state of the art, it was a lot better than it had been: I had worked in it on smallpox about ten years before and it was clear to me that things had tightened up a lot. So Bedson gambled. To finish the project in time the pace of work intensified, and more and more virus strains were cultured. But the bet failed, disastrously.

On Friday, 11 August, Janet Parker, a medical photographer in the Anatomy Department, which was located directly above the poxvirus laboratory, developed a headache and muscular pains. Her husband had to drive her to work. On Saturday she felt better and went for a walk, and on Sunday she called on a neighbour, although she began to feel ill again. On Tuesday she developed spots. On Wednesday her GP prescribed an antibiotic. It was stopped on Friday because it was thought to be causing the rash. More spots developed and she went to stay with her parents. On the following Thursday, 24 August, she was admitted to hospital. Smallpox was suspected, and it was confirmed by electron microscopy of fluid from her rash. At 10 p.m. that night she was moved to the Catherine-de-Barnes smallpox hospital, where she died on 11 September. Mrs Parker had been joined there by her mother who, despite being vaccinated on 24 August, developed smallpox on 7 September. She recovered. On 6 September, after the Government announced an investigation into the outbreak, Henry Bedson went into the shed at the bottom of his garden and cut his throat.

The investigation concluded that Mrs Parker had probably been infected by a strain of smallpox called Abid (after one of its earlier victims, a three-year-old Pakistani boy), which was being handled in the smallpox laboratory on 24 and 25 July. The virus had travelled in air currents up a service duct from the laboratory below to a room in the Anatomy Department which was used for telephone calls; on 25 July Mrs Parker had spent much more time there than usual ordering photographic materials because the financial year was about to end.

This was not the first time that a photographer working in the Anatomy Department had caught smallpox. It had happened 12 years before – almost certainly by the same route. But the laboratory had not been blamed on that occasion. There were no deaths, and no formal inquiry was held, but Allan Downie had been brought in and gave the laboratory a clean bill of health. In 1966 smallpox was still busy in the Indian subcontinent, and the photographer was described as having a ‘full and varied social life’ with ‘frequent contact with immigrant communities through visits to parties and public houses’. The smallpox he caught was variola minor (often known by its Brazilian name, ‘alastrim’), a much milder illness than classical variola major. Its victims are often not very ill, remaining socially active and frequently not seeking medical advice and, when they do, likely to be diagnosed with chickenpox or something similar. All this helps alastrim to spread. The photographer infected his father, his mother, an assistant in a chemist’s where his fiancée worked, a schoolteacher he met at a party, and an old man in a pub called the White Cock Inn, whom he didn’t even speak to. The shop assistant infected her boyfriend (who infected his sister and his two brothers) and three members of a youth club, one of whom infected her mother, her brother and, after her hospitalisation, a little boy with measles who was in the next cubicle. She also infected her cousin. The old man in the White Cock Inn infected two of his grandchildren. They infected two of their cousins, four other members of their household, a playmate and his brother. One of the grandchildren went on a Good Friday outing to Blackpool and infected at least three passengers on the bus, and, at a stop for refreshments, a hitchhiker in the café. Any attempt to track the spread of smallpox will always have links missing. There was an infection in Salford and an outbreak of eight cases centring on a primary school in Pontypool which were almost certainly caused by the same virus but couldn’t be linked to the photographer. There were also 50 cases in or near Birmingham that could be connected to him; 32 had never been vaccinated, seven had only been vaccinated in infancy (none within the previous ten years) and 11 had been vaccinated after contact with a case. Predictably, the virus was targeting those without immunity.

The nightmare for those who worry about bioterrorism is that such events might be repeated on a grand scale with variola major. At least 20 per cent of those infected would die (alastrim, at worst, kills only about 1 per cent), not only because of the intrinsic virulence of the virus but because the number of people with effective immunity has dwindled. Infant vaccination had been popular until the early 1960s. In 1962, variola major was imported into Britain from Karachi and spread to cause 62 cases and 24 deaths. More than six million people were vaccinated as a consequence.

So how real is the bioterrorist threat from smallpox? First of all, we can’t be sure that there are no stocks of virus remaining anywhere in the world except in the two official repositories: the Centers for Disease Control and Prevention in Atlanta, Georgia and the State Research Centre of Virology and Biotechnology, usually known as Vector, in Koltsovo, in the Novosibirsk region of Russia. Although Vector receives funding from the US, nobody knows whether it has been leaky. It is certain that a determined person with a reasonable degree of technical knowledge and possession of live variola major and vaccinia virus (to immunise themselves) could grow substantial amounts of the virus quickly and cheaply. Disseminating it would be a lot more difficult. It is heat-sensitive and dies as it dries, so is a much less attractive weapon than anthrax spores, which are many thousands of times more resistant. Although smallpox can be spread by air currents, close face-to-face contact is far more effective. In the 1880s, many London smallpox patients were sent to floating hospitals – the 90-gun wooden battleship Atlas, the 50-gun frigate Endymion and the ex-Channel steamer Castalia – moored in Long Reach, on the south bank of the Thames, 17 miles below London Bridge. The nearest public house was across the river on the north bank. It had an excess of smallpox cases among its customers, rumoured to be caused by the virus being blown on the wind from the hulks. But it is far more likely that it was spread by incarcerated patients who had bribed a boatman to row them across.

An important factor in terrorists’ favour is the very high probability that the first wave of cases would be misdiagnosed, delaying identification of the problem and the start of control measures. In 1973 Charles Rondle was conducting research on smallpox at the London School of Hygiene and Tropical Medicine, using techniques he had learned some years before while working for Allan Downie in Liverpool. The virus was being grown in fertile hens’ eggs. One of the membranes attached to the young embryo was ‘dropped’ by making an artificial air space between it and the shell, creating a kind of platform. After being inoculated onto it the virus grew in its cells, producing small lesions called pocks. After pock formation the egg was cut open and the membranes harvested (no special equipment was needed, and learning to do this only took an hour or two – ideal for illicit propagation of the virus). The laboratories at the School had been built in 1929, and were crowded and old-fashioned. The smallpox lab was out of bounds to casual visitors, but contained scientific instruments used for non-pox work, as well as the department’s poisons cupboard.

Ann Algeo was a Northern Irish laboratory technician who had been employed by the school since the beginning of the year. She worked on fungal diseases in another part of the building but needed access to the instruments which were kept in the smallpox laboratory. From time to time she had been there when infected membranes were being harvested. This had happened on 28 February 1973. On Sunday, 11 March she developed a bad headache, backache, vomiting and a high fever. These symptoms continued for several days and she stayed at home. A rash appeared on Thursday, 15 March, and by the following day it had covered her body. She thought that it might be a consequence of drinking too much orange juice but her GP was worried about meningitis. She was admitted to hospital the next day. She said that she worked on fungi but didn’t mention that she sometimes came into contact with smallpox. The provisional diagnosis was glandular fever. On Saturday, 17 March, St Patrick’s Day, the patient in the next bed, Nora Hurley, gave Algeo a sprig of shamrock and lent her a paper called Ireland’s Own. The same evening Mrs Hurley’s son Thomas and his wife Margaret looked at the newspaper. Ann Algeo’s boss, Dr MacKenzie, visited her on Wednesday, 21 March. He was puzzled by the blister-like lesion on her hand, and on his return to the School rang up Charles Rondle, who was at home with flu. Neither of them knew that she had watched the egg harvesting. A smallpox infection was thought highly unlikely, but MacKenzie’s deputy, who was visiting the following day, agreed to take a scraping from one of the spots for electron microscopy in order to rule it out. The doctors at the hospital weren’t told because MacKenzie thought it would come to nothing and didn’t want to make a fuss. But a few pox virus particles were seen when the sample was examined late that afternoon. MacKenzie was told the following morning and contacted the hospital. Charles Rondle came in; other specialists were consulted. By the afternoon the harvesting episode had come to light, and at 7 p.m. a Department of Health smallpox expert arrived. He was much more impressed by the electron microscopy results than the rash and arranged for the patient to be transferred to London’s smallpox hospital at Long Reach – now on land.

On Friday, 30 March Margaret Hurley developed a headache, nausea and back pain. Thomas Hurley fell ill the following day and also took to his bed. By Monday they both had severe abdominal pain, vomiting and a rash. They were admitted that evening to the infectious diseases ward of the local hospital. The most likely diagnosis was thought to be a severe viral infection – but not smallpox. However, at 12.30 p.m. on Wednesday, 4 April a social worker from Camden rang the hospital to tell them that Mrs Hurley senior had recently been in a ward at a hospital in Paddington where there had been a smallpox patient and that someone had visited her at home and vaccinated her. Mrs Hurley had called at the Camden Old People’s Welfare Association that morning about her pension book and had told the social worker that she was worried about her son and daughter-in-law. She also mentioned that someone from the Brent Public Health Department had done something to her arm a few days earlier and she wondered what it was all about. During their conversation, the penny dropped – but only thanks to the Daily Mirror. The day before there had been a brief report about a hospital ward in Paddington being closed to visitors because one of the women patients was a smallpox suspect.

Thomas and Margaret Hurley were transferred to Long Reach that evening. Margaret died on the evening of 6 April, Thomas in the early hours of 15 April. Margaret had been vaccinated in infancy; Thomas’s vaccination status was uncertain.

Between 31 December 1949 and 1 July 1971 smallpox was introduced into Europe 49 times, leading to 680 cases of variola major, 359 of which were among hospital staff, patients or visitors. So there was nothing unusual about the Hurley outbreak. It is virtually certain that the same thing would happen today if a bioterrorist went to work with the virus. The only difference now is that, because people’s immunity has diminished so much since vaccination stopped in the 1970s, the chance of first generation cases being mild and atypical – one important reason for their misdiagnosis in the past – is much reduced. But very few doctors practising today have seen a case of smallpox, and even for those who have, it would not rank on their lists of causes of backache or rashes. Nobody reads books about the diagnosis of smallpox any more. I bought my copy of Ricketts from an antiquarian bookseller. It had, at one time, been in the special medical collection of the Marylebone Public Library. Even in 1966, when the anatomy photographer walked into the White Cock Inn, the bartender remarked to customers: ‘That’s the worst case of acne I’ve ever seen.’

The scale of a terrorist-induced smallpox outbreak depends on three things: the number of people directly infected by the criminal (the first-generation cases), the speed of introduction of controls, and R0 (mathematical modeller shorthand for the average number of people successfully infected by a single case). When R0 is reduced to less than 1 the outbreak fizzles out. The greater the value of Ro the harder the task. What it would be in a smallpox outbreak today is fiercely debated: estimates range from 1.5 to greater than 20. Historical European data and pessimistic assumptions about immunity indicate a value of 5 for spread in the community, and 10 in a hospital. If these values are right, it means that outbreak growth would be slow: the size of the outbreak would then be crucially dependent on how quickly control measures were introduced.

‘The key to effective disease control is speed, speed and more speed,’ Iain Anderson writes in his report on last year’s foot and mouth outbreak in Britain. Paragraph 10.2.1 is headlined: ‘Out of control – the R0 number’.[*] Difficulties and delays in making a clinical diagnosis and implementing control measures contributed significantly to problems in handling the outbreak, and meant that it was two or three times bigger than it need have been. Control by culling is, of course, not an option for smallpox, but isolation of the patient, surrounding him with a ring of vaccinated insusceptibles, has the same effect on R0. There was vigorous debate about R0 during the foot and mouth outbreak and four teams of modellers were brought together. ‘At times there were polarised views within the group but no convincing mechanism for handling conflicts of opinion,’ Iain Anderson comments diplomatically.

Opinions about vaccination against foot and mouth disease were even more polarised. We might expect there to be less debate about vaccination against smallpox – after all, Jenner’s vaccine has been around for two hundred years, and successfully delivered smallpox eradication. But vaccination against smallpox is not a straightforward matter. If any of the current vaccines were put forward for licensing as new products they would be rejected. Complications from their use are far more common and more serious than from any other vaccine. Their origins are unknown: genetic fingerprinting has shown that they did not come from Jenner’s cowpox vaccine and records of their lineage fade into complete obscurity in the 19th century. There is a story that one strain came from a soldier during the Franco-Prussian War. There has even been a row about the relative merits of the British (Lister) and American (New York City Board of Health) vaccines. A very recent desk study by the National Security Health Policy Center in Arlington, Virginia claimed superiority for the American strain in controlling Asiatic variola major, and criticised the UK Government’s recent decision to buy a large batch of the Lister vaccine. There is no need to worry. The study was superficial (it only referenced two sources, both books, one a popular account), partisan and inaccurate – it completely missed the point that smallpox was not finally eradicated by mass vaccination but by an obsessional search for outbreaks and individual cases and their containment by isolation and targeted vaccination.

The biggest bioterrorist attack so far recorded was carried out in 1984 by followers of an Indian guru who were building a commune at The Dalles, Oregon, and ran into problems with planning permission. In an attempt to influence the results of an election for new county commissioners by incapacitating voters, they contaminated salads and coffee creamers in restaurants with Salmonella typhimurium, causing 751 cases of gastroenteritis. The Salmonella had been grown in the commune’s own laboratory.

The chances of a terrorist using smallpox to make his attack are remote. Getting hold of anthrax or plague or Salmonella typhimurium is immeasurably easier because they are still circulating in the natural world. The cult in Oregon bought their starter cultures from a commercial supplier. And even if smallpox were released, we know how to control it. In India in 1974 there were 188,003 cases. In January 1975 there were 1010 and in March, 84. The last ever case in India was in a 30-year-old Bangladeshi beggar who lived on the station platform at Karimganj in Assam. She developed her rash on 26 May 1975.

But there would be panic. Mass vaccination would be demanded, and politicians would find such calls very difficult to resist. They should remember, however, that when millions of people were vaccinated in response to the outbreak in Britain in 1962, nearly as many died from its complications as from smallpox itself. So vaccination must be targeted. Just as important is the availability of rapid diagnostic facilities. Electron microscopy played a vital role in the laboratory escape outbreaks of the 1970s. For speed of response once suspicion is raised, it is just as important today. But the UK’s machines are decaying fast: most are at least twenty years old. Microscopists used to keep their hand in by examining quality control samples sent from London, but this service stopped years ago. My laboratory now tests its capabilities by using samples provided by the Robert Koch Institute in Berlin. No one has asked me recently whether my electron microscope is still working. To be fair, guidelines are being prepared for action in the event of a deliberate release of smallpox. They assume that it is very unlikely to happen and that contingency planning is going on at local level. But we have to remember that all the smallpox hospitals closed long ago, and that the immunity of the well-vaccinated staff who worked there – if they are still alive – will have waned to virtually nothing. Let us hope that the lessons of BSE (for nearly a decade policy was driven by the assumption that the probability of people being infected was ‘remote’) and foot and mouth disease (the contingency plan was designed for an outbreak of ten cases; before the first diagnosis was made there had been at least 57, and by the end 2023) are being heeded.

Letters

Hugh Pennington points out (LRB, 5 September) that ‘nobody reads books about the diagnosis of smallpox any more. I bought my copy of Ricketts from an antiquarian bookseller.’ Even leading medical textbooks nowadays fail to discuss the clinical recognition of smallpox in any detail. Fields Virology tells us that ‘there is little point in delineating the clinical features of this now-extinct disease.’ Most rashes do not appear on the palms and soles: the smallpox rash does. Pennington describes a smallpox laboratory accident in 1973, and notes that Dr MacKenzie ‘was puzzled by the blister-like lesion on her hand’, which may ultimately have led to the diagnosis. However, in Harrison’s Principles of Internal Medicine, another leading textbook, smallpox is no longer listed among the few human rashes affecting the palms and soles.